Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors
Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors
复制标题
DOI：
10.1016/s0006-2952(01)00624-4
复制
发表时间：
2001-07-01
影响因子：
5.8
通讯作者：
Favier, A
中科院分区：
文献类型：
--
作者：
Chimienti, F;Seve, M;Favier, A
锌是一种有效的细胞凋亡抑制剂，而锌缺乏在许多细胞系中诱导细胞凋亡。为探讨锌缺乏诱导HeLa细胞凋亡的机制，用膜渗透性金属离子螯合剂N，N，N '，N'-四（2-吡啶甲基）乙二胺（TPEN）处理HeLa细胞。TPEN降低细胞内锌水平，诱导细胞凋亡，具有特征性的细胞模式，即细胞皱缩和凋亡小体形成，DNA片段化和形成典型的DNA梯状模式。TPEN处理后，caspase-3、-8和-9被激活，caspase靶蛋白、聚（ADP-核糖）聚合酶和Sp转录因子被裂解。在培养基中加入锌可抑制这些作用。为了评估锌在半胱天冬酶级联激活中的作用，我们比较了锌对肿瘤坏死因子α/放线菌酮和依托泊苷诱导的细胞凋亡与TPEN诱导的细胞凋亡的抑制作用。在肿瘤坏死因子α或依托泊苷处理的HeLa细胞中，锌的加入部分抑制caspase-3的活化，但不抑制caspase-8和caspase-9的裂解。这些结果表明，caspase-3是快速和直接激活锌螯合，而不需要上游事件。因此，Caspase-3激活是导致细胞内锌螯合后细胞凋亡的主要事件。最后，我们得出结论，细胞锌抑制细胞凋亡，保持半胱天冬酶-3失活。(C)2001 Elsevier Science Inc. All rights reserved.
Zinc is a potent inhibitor of apoptosis, whereas zinc depletion induces apoptosis in many cell lines. To investigate the mechanisms of zinc depletion-induced apoptosis, HeLa cells were treated with the membrane permeable metal ion chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). TPEN decreased the intracellular level of zinc and induced apoptosis with a characteristic cellular pattern, i.e. cell shrinkage and formation of apoptotic bodies, with DNA fragmentation and formation of a typical DNA ladder pattern. Following TPEN treatment, caspases-3, -8, and -9 were activated and caspase target proteins, poly(ADP-ribose) polymerase, and Sp transcription factors were cleaved. These effects were inhibited by adding zinc to the medium. To assess the role of zinc in the activation of the caspase cascade, we compared zinc inhibition during tumor necrosis factor alpha/cycloheximide- and etoposide-induced apoptosis with that induced by TPEN. Zinc addition partially inhibited caspase-3 activation, but not caspase-8 and -9 cleavage in HeLa cells treated with tumor necrosis factor alpha or etoposide. These results suggest that caspase-3 is rapidly and directly activated by zinc chelation, without a requirement for an upstream event. Caspase-3 activation is therefore the main event leading to apoptosis after intracellular zinc chelation. Finally, we conclude that cellular zinc inhibits apoptosis by maintaining caspase-3 inactive. (C) 2001 Elsevier Science Inc. All rights reserved.